Phosphoinositide Metabolism
Enrique Pimentel in Handbook of Growth Factors, 2017
An important primary product of phosphodiesteric cleavage of phosphoinositides breakdown is 1,2-diacylglycerol, which functions as a second messenger in the regulation of cellular proliferation. Diacylglycerol is also produced through other pathways, including neosynthesis from a glycolytic intermediate, dihydroxyacetone phosphate and production from phosphatidylcholine turnover, as well as its synthesis from monoacylglycerol.78 Diacylglycerol is generated from glycerol 3-phosphate through a pathway involving step-wise acylation to lysophosphatidic acid and phosphatidic acid. Diacylglycerol is an endogenous activator of protein kinase C, and its concentration is increased by the action of a wide diversity of hormones and growth factors. Attenuation of diacylglycerol is carried out by phosphorylation by diacylglycerol kinase or degradation by diacylglycerol lipase. Diacylglycerol kinase is a ubiquitous enzyme involved in diacylglycerol remotion by its phosphorylation to phosphatidic acid. Phorbol esters may cause a redistribution of diacylglycerol kinase from the cytosol to the plasma membrane.79 The phorbol ester-induced translocation of diacylglycerol kinase is relatively small in cells transformed by acute retroviruses carrying the v-erb-B or v-src oncogenes, which may contribute to altered cellular proliferation.80
Pharmacological Control of Eosinophil Activation and Secretion
Gerald J. Gleich, A. Barry Kay in Eosinophils in Allergy and Inflammation, 2019
PI hydrolysis also leads to the formation of 1,2-diacylglycerol, which activates PKC (56). PKC activation with phorbol esters results in release of O2− (11,38), suggesting that PKC is involved in the activation of NADPH-dependent respiratory burst oxidase. The PKC inhibitors Ro 31-8220, which acts at the ATP-binding site, and AMG-C16, which blocks the diglyceride-binding site, both inhibit LTB4 and PAF-induced O2− generation (57) and are potentiated by the diacylglycerol kinase inhibitor R 59022 (58).
General Introduction
David N. Brindley, John R. Sabine in Phosphatidate Phosphohydrolase, 2017
So far what has been discussed are the pathways for synthesizing phosphatidate de novo. This lipid can also be made by the action of diacylglycerol kinase from existing diacylglycerol. This route of metabolism is particularly important in the recycling of the diacylglycerol back into the phosphoinositides after their receptor-mediated breakdown. The possible function of phosphatidate phosphohydrolase in opposing this recycling is discussed in Chapter 2, Section V.
A novel compound heterozygous mutation in DGKE in a Chinese patient causes atypical hemolytic uremic syndrome
Published in Hematology, 2020
Jitong Li, Yinsen Song, Yaodong Zhang, Hongjiang Li, Ming Tian, Di Li, Shufeng Zhang, Guanghai Cao, Cuihua Liu
DGKE protein model predictions were performed by using the Phyre2 online tool. The C1 domain was modeled based on the c2e73A (the phorbol esters/diacylglycerol binding domain of protein kinase C gamma) template with a confidence score of 98.39, identity of 26% and coverage residues of aa 55-117 (10%) of the DGKE amino acid sequence. The integrated DAGKc, DAGKa and LC domains were modeled based on the c2qv7A (diacylglycerol kinase DgkB in complex with ADP and Mg) template with a confidence score of 100, identity of 18% and coverage residues aa 213-563 (61%) of the DGKE amino acid sequence. The 3D models were visualized with PyMOL software. The position of the residue that is altered as a result of the M1 mutation (p.C77W) is marked in pink, and the position of the residues that are altered as a consequence of the M2 mutation (p.C264Yfs*27) is marked in light green. The C1 (58-108 aa), DAGKc (219-350 aa), DAGKa (369-524 aa) and LC (548-563 aa) domains are colored blue, purple, orange and red, respectively, and the other resides of the indicated models are marked in black.
Global proteomics of fibroblast cells treated with bacterial cyclic dinucleotides, c-di-GMP and c-di-AMP
Published in Journal of Oral Microbiology, 2022
Kenneth I. Onyedibe, Samira Elmanfi, Uma K. Aryal, Eija Könönen, Ulvi Kahraman Gürsoy, Herman O. Sintim
Then, we further analyzed the downregulated proteins. In addition to differentially downregulated proteins with a measurable fold change (p ≤ 0.05 and Log2 fold change ≥ −0.5), proteins that were not detected in each of the treatment conditions but were detected in control fibroblasts were also considered to be significantly downregulated by the respective treatment, hence were undetectable. Amongst the 50 proteins downregulated in fibroblasts treated with both dinucleotides, Queuosine salvage protein, and E3 ubiquitin-protein ligase (MARCH5) were downregulated by both c-di-GMP and c-di-AMP. Another related E3 ubiquitination ligase, E3 ubiquitin-protein ligase RNF 181 (RNF181), was downregulated by only c-di-AMP. Similarly, some essential kinases such as Serine/threonine-protein kinase N2 (PKN2) and Uridine-cytidine kinase 2 (UCK2) were also downregulated by both c-di-GMP and c-di-AMP. Nevertheless, other critical kinases were downregulated by c-di-AMP and not c-di-GMP. For instance, Diacylglycerol kinase (DGK), Glycerol kinase (GK) and Mitogen-activated protein kinase (MAPK) were downregulated in the presence of only c-di-AMP. Conversely, a phosphatase, Glycerol-3-phosphate phosphatase (G3PP) and a phosphatase inhibitor, cAMP-regulated phosphoprotein 19 (ARPP19) were exclusively downregulated by c-di-GMP only. A complete list of proteins downregulated in the various treatment groups is provided in SI, Table S5. Downregulated proteins with a measurable fold change (p ≤ 0.05 and Log2 fold change ≥ −0.5) are listed separately with their fold change in Table S6 (c-di-AMP) and Table S7 (c-di-GMP).
Exosomes Represent an Immune Suppressive T Cell Checkpoint in Human Chronic Inflammatory Microenvironments
Published in Immunological Investigations, 2020
Gautam N Shenoy, Maulasri Bhatta, Jenni L Loyall, Raymond J Kelleher Jr, Joel M Bernstein, Richard B Bankert
However, when T-cells derived from nasal polyps were tested for their response to activation via the T-cell receptor, it was established that both CD4 + and CD8 + T-cells were profoundly hypo-responsive to an activation stimulus (Lehman et al. 2012). These T-cells had a phenotype of effector memory cells and their anergy was manifested by a blockade in the activation signaling cascade before or just after diacylglycerol (Lehman et al. 2012). Similar hypo-responsiveness has now been demonstrated in the T-cells derived from the chronic inflammatory microenvironments of tumor tissues and this T cell arrest was postulated to result from the phosphorylation of diacylglycerol into an inactive phosphatidic acid by diacylglycerol kinase (Kelleher et al. 2015).
Related Knowledge Centers
- Bacteria
- Conserved Sequence
- Diglyceride
- Glycerophospholipid
- Membrane Protein
- Phosphatidic Acid
- Phosphatidylinositol
- Transmembrane Domain
- Adenosine Triphosphate
- Lipid Signaling